Interleukin-1/Toll-like receptor signaling potentiates macrophage olfactory receptor 2-driven atherosclerosis

Olfactory receptor 6A2 (OR6A2) signaling stimulates atherogenic NLRP3 inflammasome activation in vascular macrophages (Mϕs). Current evidence suggests that interleukin-1 receptor type 1 (IL-1R1)/Toll-like receptor (TLR) signaling may modulate this OR6A2-mediated inflammasome response. However, the role of and mechanism(s) by which IL-1R1/TLR signaling modulates the inflammasome response and resultant atherosclerosis remain unknown. We discovered that the interaction between β-arrestin-2 (βarr2) and OR6A2's intracellular loop 3 (OR6A2^ICL3) mediates OR6A2 endocytosis, thereby inhibiting OR6A2-mediated Mϕ inflammasome activation. IL-1R1/TLR signaling promotes coupling of the coiled-coil domain of tumor necrosis factor receptor-associated factor 6 (TRAF6^CCD) with βarr2, thereby blocking OR6A2^ICL3-βarr2 binding, inhibiting βarr2/AP2-mediated OR6A2 internalization, and potentiating Mϕ inflammasome activation. Consistently, blocking TRAF6^CCD-βarr2 coupling in vascular Mϕs inhibits octanal-induced atherosclerosis in high-cholesterol-diet-fed Ldlr^-/- mice. Additionally, IL-1R1/TLR-activated βarr2^K295 deSUMOylation drives TRAF6^CCD-βarr2 coupling in Mϕs, and βarr2^K295 deSUMOylation in vascular Mϕs promotes OR6A2-mediated atherosclerosis in high-cholesterol-diet-fed Ldlr^-/- mice. In conclusion, IL-1R1/TLR-induced TRAF6^CCD-βarr2 coupling, by inhibiting βarr2/AP2-mediated OR6A2 endocytosis, promotes atherogenic OR6A2-mediated NLRP3 inflammasome activation in vascular Mϕs.